PROJECT SUMMARY Second-generation antipsychotics (SGAs) such as olanzapine and clozapine are essential medications for millions of schizophrenia patients worldwide. Moreover, the last decade has witnessed an exponential increase of their uses for other neuropsychiatric conditions including bipolar disorder, major depressive disorder, and autism. Despite their broad efficacy and low risks for extrapyramidal symptoms, most SGAs have been linked to substantial drug-induced metabolic syndrome that is characterized by excessive weight gain, dyslipidemia, and type-2 diabetes. Obesity and diabetes often develop shortly after SGA treatment. Moreover, the risk for metabolic syndrome is significantly higher in female subjects. The rapid disease onset as well as the gender difference strongly suggest a distinct etiology underlying SGA-induced metabolic syndrome. Unfortunately, while tremendous resources and efforts have been spent combating obesity and diabetes in the general population, little progress has been made toward understanding or treating drug-induced metabolic disturbances. Genome-wide association studies in human patients have implicated a role for brain serotonin (5-HT) receptors in SGA-induced metabolic syndrome. However, previous efforts to discern their roles have been hindered by the difficulty to replicate SGA-induced metabolic syndrome in mice. Using a modified olanzapine diet, we are able to reliably reproduce excessive weight gain and diabetes in C57BL/6 mice. The success in modeling olanzapine-induced metabolic syndrome in mice provides us an opportunity to precisely characterize metabolic alterations in olanzapine-treated mice. Furthermore, it allows us to apply sophisticated mouse genetic tools to unraveling candidate genes and pathways that mediate olanzapine?s metabolic effects. Here, we will carry out a series of in vivo analyses in transgenic mice to interrogate the contribution of individual serotonin receptors to olanzapine-induced metabolic syndrome. We hypothesize that olanzapine acts through serotonin 2c receptor (Htr2c) and serotonin 1b receptor (Htr1b) in distinct populations of hypothalamic neurons to impair energy and glucose metabolism. This hypothesis is evidence-based, including exciting, solid preliminary data that is presented here for the first time in which we show that olanzapine?s effect on food intake and weight gain is blunted in mice lacking Htr2c or Htr1b. Experiments will include targeting Htr2c specifically in hypothalamic POMC neurons and Htr1b in hypothalamic AgRP neurons to determine whether Htr2c and Htr1b act on these sites to mediate the untoward metabolic effects of olanzapine. We will also test the therapeutic potential of specific agonist for Htr2c in olanzapine-fed mice. Therefore, positive results from these studies will provide necessary evidence and rationale for the clinical use of specific 5-HT receptor agonists to treat SGA-induced metabolic syndrome in millions of patients.